DESCRIPTION (provided by applicant: This application for CAP Dr. Taosheng Huang is a two-year supplement to the UCSD GCRC grant Satellite Center at UC Irvine. If awarded, Dr. Huang will complete the following aims. The goal of the study is to understand the molecular basis of the phenotypic variations of Holt-Oram syndrome (HOS), an autosomal dominant condition characterized by congenital cardiac defects and forelimb anomalies. Mutation of TBX5 was demonstrated to cause HOS. Clinical manifestations of HOS can vary over a wide range, which make managing and counseling patients and families problematic. A preliminary genotype-phenotype correlation has been established. However, the mutation detection rate was low in the coding region of TBX5. To further study the molecular basis of the phenotypic variability of HOS and improve the mutation detection rate, the following specific aims will be addressed. 1. To expand the mutation spectrum of TBX5 and further amplify genotype-phenotype correlation by recruiting more patients with HOS. 2. To improve the mutation detection rate by searching for the mutation in the promoter regions and other noncoding regions of TBX5, and therefore also to identify the important elements for TBX5 expression. 3. To study the association of polymorphisms in the TBX5 gene with phenotypic expression in the patient with known mutations in TBX5. 4. To study monoallelic expression of TBX5 by examining limb bud tissues from heterozygous Tbx5 knockout mice. INVESTIGATORS:Dr. Huang trained in medicine at the Fujian Medical College in China graduating in 1987, and then took a Ph.D. in biomedical science at Mt. Sinai Medical School in New York, graduating in 1991. He completed postdoctoral work at the American Red Cross in Rockville in 1993 and subsequently performed a complete three-year pediatric residency at Georgetown University Medical Center, followed by a fellowship in Genetics at Children's Hospital in Boston. After this, he joined the laboratory of Drs. Christine and Johnathan Seidman in 1997, at which point he listed nine peer-reviewed publications all prior to 1993. On the basis of proposed studies designed to better define the molecular and genetic basis of the HOS at Children's he was awarded a CAP award effective 7/1/99. This application is to extend that award by two years for studies to be conducted in the GCRC at UC Irvine, where Dr. Huang assumed a position as Associate Professor of Pediatrics in 2001. He has published four papers in peer-reviewed journals until now, three of which he serves as the primary author and the fourth of which is published in PNAS with the Drs. Seidman on different TBX5 interactions in heart and limb defined by HOS. In order to move this funding from Boston to Irvine, Dr. Susan Bryant was approved as a new mentor for Dr. Huang. Dr. Susan Bryant is an outstanding scientist and Dean of the School of Biological Sciences at UC Irvine. She was educated at King's College, London and St Mary's Hospital Medical School, before doing postdoctoral work at Case Western Reserve University in Cleveland. She has made many contributions to the understanding of congenital anomalies, and currently serves on the Executive Editorial Board of the Journal of Zoology and on the editorial boards of Developmental Biology and the Journal of Biosciences. She is well qualified as a mentor, but no recent training history is provided and this is important for scientists in high administrative positions, for whom the distractions from mentoring can be legion. Dr. Suzanne Cassidy is also well qualified. She received a Ph.D. degree in 1969 from Brandeis, and a M.D. degree in 1976 from Vanderbilt before conducting a residency in pediatrics at the University of Washington in Seattle. Her early academic career was at the University of Cincinnati where she rose to Associate Professor before moving to the University of Arizona in 1988, where she was the program director of the human genetics fellowship training program. Between 1993 and 2000, she was Professor of Genetics and pediatrics at Case Western Reserve, before moving to UC Irvine in 2000, where she is Professor of Clinical Pediatrics. She currently serves an Associate Editor of Genetics in Medicine. She is clearly well qualified to mentor in medical genetics.